Abstract Cytomegalovirus (CMV) and respiratory virus infections are common causes of morbidity and mortality following allo-HCT. Recent studies in animal models demonstrated that the intestinal microbiota contributes to anti-viral resistance. Our studies demonstrate that loss of bacterial diversity in fecal microbiota of allo-HCT patients at the time of stem cell engraftment is associated with higher rates of viral infections in the post-engraftment period and that loss of butyrate- producing commensal bacteria increases the risk of viral lower respiratory tract infection (LRTI). Our goal is to determine whether members of the intestinal microbiota contribute to antiviral resistance and to eventually modify microbiota composition and diversity to optimize resistance against viral infection and reactivation. The first aim is to correlate fecal microbiota composition following allo-HCT with risk of sustained CMV viremia and to extend our studies demonstrating that loss of butyrate-producing commensal bacteria increases the risk of LRTI. We will investigate CMV seropositive patients following allo-HCT and correlate the intestinal microbiome with risk of protracted, high-level CMV viremia following engraftment. The second aim will determine whether microbiota from allo-HCT patients who either developed severe viral infections or maintained a high level of resistance, upon transplantation into germ free (GF) mice, determines resistance/susceptibility to MCMV and Influenza Virus infection. The third aim is to test specific commensal species in gnotobiotic mice for their ability to confer resistance to viral infections. We will use computational platforms to identify microbial metabolic pathways that correlate with resistance to viral infections. Microbial consortia that approximate the metabolic networks detected in resistant hosts will be cultured and administered to gnotobiotic mice or mice that have been treated with broad-spectrum antibiotics. Although experimental studies have demonstrated a role for the intestinal microbiota in systemic anti-viral defense the bacterial species mediating resistance have yet to be defined. Our studies will identify specific bacterial taxa that are associated with resistance to viral infections that occur following allo-HCT. These studies will facilitate the identification of mechanisms of anti-viral resistance and may provide approaches to reduce the incidence of severe viral infections following allo-HCT.